The present invention relates to a process for preparing tert-butyl 4xe2x80x2-methyl-2-biphenylcarboxylate. More particularly, the present invention relates to a process for preparing tert-butyl 4xe2x80x2-methyl-2-biphenylcarboxylate, which is useful as an intermediate of pharmaceuticals such as antihypertensives.
Conventionally, there have been known processes for preparing tert-butyl 4xe2x80x2-methyl-2-biphenylcarboxylate, including (A) a process of reacting p-methylphenylzinc chloride with 2-tert-butoxycarbonyliodobenzene in the presence of NiCl2(Ph[phenyl group, hereinafter referred to the same]3P)2 as a catalyst (Japanese Patent Laid-Open No. Hei 6-1790); and (B) a process of reacting 4xe2x80x2-methyl-2-biphenylcarboxylic acid with isobutene in anhydrous ether in the presence of concentrated sulfuric acid as a catalyst (Japanese Unexamined Patent Publication No. Hei 5-506443).
However, there are some defects in the process (A) such that complicated procedures are necessitated in the preparation of p-methylphenylzinc chloride as a starting material, since there is a necessity to prepare the p-methylphenylzinc chloride at an extremely low temperature of xe2x88x9278xc2x0 C., and that relatively expensive reagents such as 2-tert-butoxycarbonyliodobenzene and NiCl2(Ph3P)2 are needed.
In the process (B), since an ether is used, there has been desired to develop a process in which a highly hazardous solvent such as the ether is not used.
Accordingly, in recent years, there have been desired to establish a process capable of conveniently and industrially advantageously preparing tert-butyl 4xe2x80x2-methyl-2-biphenylcarboxylate in a high yield.
An object of the present invention is to provide a process capable of easily preparing tert-butyl 4xe2x80x2-methyl-2-biphenylcarboxylate having high quality in a high yield without requiring complicated procedures or any hazardous solvents.
According to the present invention, there is provided a process for preparing tert-butyl 4xe2x80x2-methyl-2-biphenylcarboxylate, characterized in that 4xe2x80x2-methyl-2-biphenylcarboxylic acid is reacted with isobutene in the presence of an acid catalyst.
According to the present invention, tert-butyl 4xe2x80x2-methyl-2-biphenylcarboxylate can be prepared by reacting 4xe2x80x2-methyl-2-biphenylcarboxylic acid with isobutene in the presence of an acid catalyst.
4xe2x80x2-Methyl-2-biphenylcarboxylic acid, a starting material in the present invention, can be prepared by hydrolyzing 2-cyano-4xe2x80x2-methylbiphenyl in a glycol in the presence of an alkali.
The alkali includes, for instance, sodium hydroxide, potassium hydroxide, and the like.
It is desired that the amount of the alkali used is usually 1 to 4 mol, preferably 2 to 3 mol, per one mol of the above-mentioned 2-cyano-4xe2x80x2-methylbiphenyl.
The hydrolysis of the above-mentioned 2-cyano-4xe2x80x2-methylbiphenyl can be carried out by dissolving 2-cyano-4xe2x80x2-methylbiphenyl and an alkali in a glycol to give a solution, and thereafter stirring the solution with heating as occasion demands.
In the present invention, the glycol is used as a solvent. It is preferable that the glycol is mixed with water from the viewpoint of speedily progressing the reaction. When the glycol is mixed with water, the amount of water used is not limited to specified ones, and it is desired that the amount of water is usually 1 to 100 parts by weight or so, preferably 5 to 50 parts by weight or so, based on 100 parts by weight of the glycol.
The above-mentioned glycols include, for instance, ethylene glycol, propylene glycol, butanediol, diethylene glycol, and the like. Among them, glycols having high boiling points (198xc2x0 to 215xc2x0 C.), such as ethylene glycol and propylene glycol, are preferable.
It is preferable to adjust the amount of the glycol used so that the amount of the above-mentioned 2-cyano-4xe2x80x2-methylbiphenyl is 1 to 100 parts by weight or so, preferably 25 to 50 parts by weight or so, based on 100 parts by weight of the solvent.
The hydrolysis of the above-mentioned 2-cyano-4xe2x80x2-methylbiphenyl can be usually carried out in the range of 100xc2x0 to 200xc2x0 C. The higher the temperature is, the reaction completes in a shorter period of time.
The atmosphere in which 2-cyano-4xe2x80x2-methylbiphenyl is hydrolyzed is not limited to specified ones. Usually, the atmosphere may be air, or an inert gas such as nitrogen gas or argon gas. In addition, it is preferable that the reaction pressure is usually normal pressure to 10 kgf/cm2 (gauge pressure, hereinafter referred to the same) or so. In the present invention, it is preferable to carry out hydrolysis with removing ammonia gas formed by the reaction from the reaction system.
The termination of reaction can be confirmed, for instance, by high-performance liquid chromatography, and the like.
After the termination of reaction, desired 4xe2x80x2-methyl-2-biphenylcarboxylic acid can be isolated by, for instance, adding water, toluene, or the like to the reaction solution, removing its neutral portion by extraction; further adding hydrochloric acid to release the resulting product; and collecting the product as crystals by filtration. Further, 4xe2x80x2-methyl-2-biphenylcarboxylic acid having a higher purity can be obtained by dissolving the resulting crystals in toluene, or the like, and recrystallizing the crystals therefrom.
tert-Butyl 4xe2x80x2-methyl-2-biphenylcarboxylate can be prepared by reacting the thus obtained 4xe2x80x2-methyl-2-biphenylcarboxylic acid with isobutene in the presence of an acid catalyst.
The amount of isobutene which is used in the reaction with 4xe2x80x2-methyl-2-biphenylcarboxylic acid is not limited to specified ones. It is desired that the amount of isobutene is at least 1.5 mol, preferably at least 2 mol, more preferably at least 3 mol, from the viewpoint of reactivity, and at most 10 mol, preferably at most 7 mol, from the viewpoint of economics, per one mol of 4xe2x80x2-methyl-2-biphenylcarboxylic acid.
As the acid catalyst, sulfuric acid, sulfonic acids and phosphorus halides are preferable from the viewpoints of reactivity and economics.
The sulfonic acid includes, for instance, methanesulfonic acid, p-toluenesulfonic acid, and the like. Also, the phosphorus halide includes, for instance, phosphorus oxytrichloride, phosphorus trichloride, phosphorus pentachloride, and the like. Among these phosphorus halides, phosphorus oxytrichloride and phosphorus trichloride are preferable from the viewpoint of reactivity. Incidentally, it is preferable that sulfuric acid is usually a concentrated sulfuric acid having a concentration of 96 to 98% by weight.
It is desired that the amount of the acid catalyst is at least 0.1 mol, preferably at least 0.2 mol, from the viewpoint of reactivity, and at most 1.2 mol, preferably at most 1.1 mol, from the viewpoint of economics, per one mol of 4xe2x80x2-methyl-2-biphenylcarboxylic acid.
In the present invention, when sulfuric acid is used as an acid catalyst, it is preferable that 4xe2x80x2-methyl-2-biphenylcarboxylic acid is reacted with isobutene in the presence of a dehydrating agent. Incidentally, although the dehydrating agent is not particularly necessary when a sulfonic acid, a phosphorus halide, or the like is used as an acid catalyst, the dehydrating agent may be used if desired.
The dehydrating agent includes, for instance, anhydrous magnesium sulfate, and the like. The anhydrous magnesium sulfate can be preferably used from the viewpoint of reactivity.
It is desired that the amount of the dehydrating agent used is at least 0.1 mol, from the viewpoint of reactivity, and at most 3 mol, preferably at most 2 mol, from the viewpoint of economics, per one mol of 4xe2x80x2-methyl-2-biphenylcarboxylic acid.
In the present invention, when the reaction is carried out by using sulfuric acid as an acid catalyst, 4xe2x80x2-methyl-2-biphenylcarboxylic acid can be reacted with isobutene, for instance, by mixing the acid catalyst, the dehydrating agent, and a solvent mentioned below, adding 4xe2x80x2-methyl-2-biphenylcarboxylic acid to the resulting mixture, and introducing isobutene gas thereto, and the like.
Also, when the reaction is carried out using a sulfonic acid or a phosphorus halide as an acid catalyst, 4xe2x80x2-methyl-2-biphenylcarboxylic acid can be reacted with isobutene, for instance, by mixing 4xe2x80x2-methyl-2-biphenylcarboxylic acid with a solvent mentioned below, adding the phosphorus halide to the resulting mixture, and introducing isobutene gas thereto, and the like. When the reaction is carried out using a phosphorus halide as an acid catalyst, its ability as an acid catalyst can be adjusted by adding water. It is desired that the amount of water added at this stage is 0.1 to 1.2 mol, preferably 0.5 to 1.0 mol, per one mol of the phosphorus halide, from the viewpoint of reactivity.
Incidentally, it is preferable that the amount of isobutene gas used is adjusted so that the amount of isobutene used in the reaction can be the amount as mentioned above.
In the present invention, a solvent can be used in the reaction. The solvent includes, for instance, hydrocarbon solvents such as cyclohexane and toluene; halogenated solvents such as dichloromethane and dichloroethane, and the like. It is preferable that the amount of the solvent used can be adjusted so that the amount of 4xe2x80x2-methyl-2-biphenylcarboxylic acid can be usually 2 to 70 parts by weight or so, based on 100 parts by weight of the solvent.
The reaction temperature of 4xe2x80x2-methyl-2-biphenylcarboxylic acid with isobutene cannot be absolutely determined because the reaction temperature can differ depending upon the presence or absence of a dehydrating agent, and the like. For instance, when the reaction is carried out in the absence of a dehydrating agent, it is desired that the above-mentioned reaction temperature is usually 0xc2x0 to 40xc2x0 C., preferably 20xc2x0 to 30xc2x0 C. Also, for instance, when anhydrous magnesium sulfate or the like is used as a dehydrating agent, it is desired that the above-mentioned reaction temperature is usually 0xc2x0 to 45xc2x0 C., preferably 15xc2x0 to 35xc2x0 C., because magnesium sulfate releases its crystal water at about 48xc2x0 C., thereby losing its dehydration ability.
The reaction time cannot be absolutely determined because the reaction time can differ depending upon reaction conditions such as reaction temperature. The reaction time can be a period of time necessary for completing the reaction. The reaction time is usually from 1 to 24 hours or so. Incidentally, the termination of the reaction can be confirmed by means of, for instance, high-performance liquid chromatography (HPLC), and the like.
The thus obtained reaction product can be isolated, for instance, by adding water to the reaction solution after the termination of the reaction, sufficiently stirring the solution to allow phase separation, thereafter washing the organic layer with an aqueous sodium hydroxide, or the like, and concentrating the organic layer by distilling off the organic solvent.
tert-Butyl 4xe2x80x2-methyl-2-biphenylcarboxylate obtained according to the present invention can be preferably used as an intermediate of pharmaceuticals such as antihypertensives.